| Title: | No genetic evidence for an association of apolipoprotein A-I with cardiovascular outcomes at different LDL cholesterol levels: drug-target Mendelian randomization analyses |
| Journal: | Atherosclerosis |
| Published: | 16 Jun 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42335479/ |
| DOI: | https://doi.org/10.1016/j.atherosclerosis.2026.120815 |
| URL: | https://www.atherosclerosis-journal.com/article/S0021-9150(26)00181-4/pdf |
Publication 20629
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
BACKGROUND AND AIMS: Exploratory post-hoc analyses of the AEGIS-II trial suggested that the efficacy of CSL112 (apolipoprotein A-I infusion) may be greater in patients with high baseline LDL-C. This genetic study aimed to assess whether LDL-C levels modify the effect of apoA-I on cardiovascular outcomes.</p>
METHODS: We conducted drug-target Mendelian randomization analyses using data from 339,210 UK Biobank participants. Genetic proxies for apoA-I elevation (cis-acting variants within APOA1 gene) were used to mimic the effect of CSL112 therapy. The primary outcome was a composite of ischemic heart disease, myocardial infarction, and stroke; secondary outcomes were the individual components. To mitigate collider bias, we stratified by residual LDL-C, derived from a model adjusting LDL-C for the genetic instrument, age, sex, genotyping array and top 40 genetic principal components. Sensitivity analyses included alternative genetic instruments and formal tests for effect modification.</p>
RESULTS: Genetically proxied apoA-I elevation was associated with elevated circulating apoA-I and HDL-C, but there was no concomitant association with any cardiovascular outcome. Null findings were consistent across strata of residual LDL-C. Sensitivity analyses with alternative instrument sets and formal interaction tests uniformly confirmed the absence of any association or effect modification.</p>
CONCLUSIONS: Genetically proxied lifelong elevation of apoA-I concentration was not associated with reduced cardiovascular risk, even among individuals with high residual LDL-C.</p>
5 Authors
- Shan Luo
- Yujie Ai
- Stephen Burgess
- Shiu Lun Au Yeung
- Mika Ala-Korpela
1 Application
| Application ID | Title |
|---|---|
| 51001 | Using Mendelian randomization to infer health effects of cardiovascular and diabetes medication in the UK Biobank |
Enabling scientific discoveries that improve human health